BRAF mutation analysis in thyroid nodules with indeterminate cytology: our experience on surgical management of patients with thyroid nodules from an area of borderline iodine deficiency.

PURPOSE: Fine-needle aspiration (FNA) with cytologic evaluation is the most reliable tool for malignancy prediction in thyroid nodules, but cytologic diagnosis remains indeterminate for 12-18 % of nodules. BRAF V600E mutation has been reported to show a high specificity for malignant thyroid nodules and the use of this marker to refine indeterminate FNA cytology results may be a useful diagnostic adjunctive tool in the pre-operative evaluation of thyroid nodules. The aim of this study was to estimate the prevalence of BRAF exon 15 mutation (V600E) and its clinical value as a diagnostic tool in a series of thyroid nodules with indeterminate cytology from an area of borderline iodine deficiency. SUBJECTS AND METHODS: One hundred and fifty-three thyroid samples obtained by FNA of thyroid nodules from 151 patients were subjected to the analysis of BRAF V600E mutation by direct sequencing. In the study 54 nodules with indeterminate cytology, 56 benign and 43 malignant thyroid nodules were included. RESULTS: V600E BRAF gene mutation was demonstrated in 19/43 malignant nodules, in 0/56 benign nodules and in only 1/54 indeterminate nodules that, after histology, turned out to be at a papillary thyroid carcinoma. CONCLUSIONS: The application of BRAF exon 15 analysis showed limitations when applied to discriminate thyroid nodules with indeterminate cytology if wild-type BRAF is found, and there is no role for avoiding diagnostic thyroid surgery.

Genetic markers to discriminate benign and malignant thyroid nodules with undetermined cytology in an area of borderline iodine deficiency.

BACKGROUND: Fine needle aspiration (FNA) with cytologic evaluation is the most reliable tool for malignancy prediction in thyroid nodules, but cytologic diagnosis remains undetermined for 20% of nodules. AIM: We investigated the diagnostic potential of a set of 6 marker genes to distinguish benign and malignant thyroid nodules. SUBJECTS AND METHODS: The prospective study included 153 thyroid samples obtained by FNA of thyroid nodules from 151 patients (56 benign, 43 malignant, and 54 nodules with undetermined cytology). Gene expression was evaluated by quantitative realtime PCR and statistical analysis of data was performed. All samples were analyzed for V600E BRAF mutation. RESULTS: A decrease in TTF3 and HGD1 expression was observed in malignant nodules with respect to benign ones, while an increase in PLAB expression was demonstrated in these nodules. The decision model was valid for 88 of 99 cases of benign and malignant nodules, with a total of 11 false positive or negative predictions. The obtained malignant/benign phenotype prediction was also valid for 37 of 54 cases of nodules with undetermined cytology with a total of 8 false positive and 9 false negative predictions. V600E BRAF gene mutation was demonstrated in 19/43 malignant nodules, in 0/56 benign nodules, and in 1/54 undetermined nodules. CONCLUSIONS: The expression profiles of genes (TFF3, HGD1, and PLAB) allowed a good prediction for the differentiation of benign thyroid lesions and thyroid cancer starting from cells of FNA; however, this assay showed limitations when applied to discriminate thyroid nodules with undetermined cytology.

Hashimoto's thyroiditis is associated with papillary thyroid carcinoma: role of TSH and of treatment with L-thyroxine.

The possible association between Hashimoto's thyroiditis (HT) and papillary thyroid carcinoma (PTC) is a still debated issue. We analyzed the frequency of PTC, TSH levels and thyroid autoantibodies (TAb) in 13 738 patients (9824 untreated and 3914 under l-thyroxine, l-T(4)). Patients with nodular-HT (n=1593) had high titer of TAb and/or hypothyroidism. Patients with nodular goiter (NG) were subdivided in TAb-NG (n=8812) with undetectable TAb and TAb+NG (n=3395) with positive TAb. Among untreated patients, those with nodular-HT showed higher frequency of PTC (9.4%) compared with both TAb-NG (6.4%; P=0.002) and TAb+NG (6.5%; P=0.009) and presented also higher serum TSH (median 1.30 vs 0.71 µU/ml, P<0.001 and 0.70 µU/ml, P<0.001 respectively). Independently of clinical diagnosis, patients with high titer of TAb showed a higher frequency of PTC (9.3%) compared to patients with low titer (6.8%, P<0.001) or negative TAb (6.3%, P<0.001) and presented also higher serum TSH (median 1.16 vs 0.75 µU/ml, P<0.001 and 0.72 µU/ml, P<0.001 respectively). PTC frequency was strongly related with serum TSH (odds ratio (OR)=1.111), slightly related with anti-thyroglobulin antibodies (OR=1.001), and unrelated with anti-thyroperoxidase antibodies. In the l-T(4)-treated group, when only patients with serum TSH levels below the median value (0.90 µU/ml) were considered, no significant difference in PTC frequency was found between nodular-HT, TAb-NG and TAb+NG. In conclusion, the frequency of PTC is significantly higher in nodular-HT than in NG and is associated with increased levels of serum TSH. Treatment with l-T(4) reduces TSH levels and decreases the occurrence of clinically detectable PTC.

Real-time elastosonography: useful tool for refining the presurgical diagnosis in thyroid nodules with indeterminate or nondiagnostic cytology.

BACKGROUND: Indeterminate and nondiagnostic patterns represent the main limitation of fine-needle aspiration (FNA) cytology of thyroid nodules, clinical and echographic features being poorly predictive of malignancy. The newly developed real-time ultrasound elastography (USE) has been previously applied to differentiate malignant from benign lesions. The aim of this study was to get further insights into the role of USE in the presurgical diagnosis of nodules with indeterminate or nondiagnostic cytology. PATIENTS: The study included 176 patients who had one (n=138) or multiple (n=38) nodules with indeterminate or nondiagnostic cytology on FNA, for whom histology was available after thyroidectomy. A total of 195 nodules (142 indeterminate, 53 nondiagnostic) were submitted to USE, and elasticity was scored as 1 (high), 2 (intermediate), or 3 (low). RESULTS: In indeterminate lesions, the score 1, describing high elasticity, was strongly predictive of benignity, being found in 102 of 111 benign nodules and in only one of 31 carcinomas (P<0.0001). By combining the scores 2 and 3, USE had a sensitivity of 96.8% and a specificity of 91.8%. In nodules with nondiagnostic cytology, score 1 was found in 39 of 45 benign nodules and in only one of eight carcinomas (P<0.0001). By combining the scores 2 and 3, USE had a sensitivity of 87.5% and a specificity of 86.7%. CONCLUSIONS: USE may represent an important tool for the diagnosis of thyroid cancer in nodules with indeterminate or nondiagnostic cytology and may prove useful in selecting patients who are candidates for surgery.

L-thyroxine-treated patients with nodular goiter have lower serum TSH and lower frequency of papillary thyroid cancer: results of a cross-sectional study on 27 914 patients.

The risk of papillary thyroid cancer (PTC) is related to serum TSH, and the development of thyroid autonomy by reducing TSH levels decreases the frequency of PTC in patients with nodular goiter. Our aim was to investigate the effect of L-thyroxine (LT(4)) on the frequency of PTC diagnosed by cytology in a large series of patients with nodular goiter untreated (n=20 055) or treated with L-T(4) (n=7859). L-T(4)-treated patients with respect to untreated patients presented significantly lower serum TSH (median, interquartile range: 0.30 muU/ml, 0.08-0.62 microU/ml versus 0.70 muU/ml, 0.38-1.14 muU/ml; P<0.0001) and prevalence of PTC (3.2 vs 5.1%; P<0.0001). The frequency of PTC was closely related to serum TSH, with it being lowest in patients with TSH below the normal range (<0.4 muU/ml; 189/10 059, 1.9%) and highest in patients with TSH above the normal range (>3.4 muU/ml; 21/127, 16.5%), also showing a progressive increase from the lower to the upper quartile of normal range. A significantly higher proportion of L-T(4)-treated patients (6650/7859, 84.6%) had serum TSH below the median (0.90 muU/ml) with respect to untreated patients (12,599/20,055, 62.8%; chi(2) P value <0.0001), with it being included in the range of TSH associated with a lower frequency of PTC. The relationship between serum TSH and frequency of PTC was unrelated to the type of nodularity (solitary versus multinodular) and was not age dependent. In conclusion, patients with nodular goiter, treatment with L-T(4) is responsible for the reduction of serum TSH and is associated with a decreased frequency of PTC.

Male sex, single nodularity, and young age are associated with the risk of finding a papillary thyroid cancer on fine-needle aspiration cytology in a large series of patients with nodular thyroid disease.

OBJECTIVE: To evaluate the risk of papillary thyroid carcinoma (PTC) at fine-needle aspiration (FNA) cytology in 34 120 patients. RESULTS: False positive and false negative rates of FNA cytology were 1.2 and 1.8% in comparison with the histology in 3406 nodules from 3004 patients who underwent surgery. PTC (901 cases) was more frequent in solitary nodule (SN; 446/13 549, 3.3%) than in multinodular goiter (MNG; 411/19 923, 2%, chi(2)=48.8; P<0.0001), and in males (209/6382, 3.3%) than in females (648/26 945, 2.40%, chi(2)=15.58; P<0.0001). PTC prevalence in Graves' disease (GD; 13/286, 4.5%) and Hashimoto's thyroiditis (HT; 31/508, 6.1%) was higher than in SN, this difference being significant in HT (chi(2)=8.7; P=0.003), but not in GD (chi(2)=1.6; P=0.2). Using the multiple logistic regression analysis, independent risk predictors of PTC were determined, which were younger age (odds ratio (OR)=0.97, confidence interval (CI) 0.964-0.974; P<0.0001), male gender (OR=1.44, CI 1.231-1.683; P<0.0001), and SN versus MNG (OR=0.63, CI 0.547-0.717; P<0.0001). The individual risk predictivity was highly improved by including serum TSH in the prediction model, which was measured at FNA in 11 919 patients. CONCLUSION: A cytology suspicious or indicative of PTC was associated with younger age, male gender, and solitary versus multiple nodularity. These clinical parameters, together with serum TSH, may allow formulation of an algorithm that could be usefully applied to predict the risk of PTC in individual patients when cytology does not give a diagnostic result.

Papillary thyroid cancer, although strongly associated with lymphocytic infiltration on histology, is only weakly predicted by serum thyroid auto-antibodies in patients with nodular thyroid diseases.

OBJECTIVE: We evaluated the association between thyroid autoimmunity and thyroid cancer in a retrospective series of unselected thyroid nodules submitted to fine-needle aspiration (FNA) cytology. DESIGN: Anti-thyroid antibodies (TAb) were measured in patients with multinodular goiter (MNG) and single/isolated thyroid nodule (S/I) submitted to FNA. Thyroid lymphocytic infiltration (LI) on histology was studied in a subgroup of patients submitted to thyroidectomy; 13,021 patients were included: on cytology 622 had papillary thyroid cancer (c- PTC) and 12,399 benign thyroid nodular diseases (c-BTN). LI was evaluated in histological samples of 688 patients: 304 with PTC (h-PTC) and 384 with BTN (h-BTN). RESULTS: TAb prevalence was not different in c-BTN and c-PTC (38.7% vs 35.6%). TAb were more frequent in c-BTN than c-PTC in females with MNG (40.1% vs 32.5%, p=0.02), and in c-PTC than in c-BTN in males with S/I (31.2% vs 20.4%, p=0.02) and, although not significantly, in females younger than 30 yr (35.1% vs 30.7%). The frequency and severity of LI was significantly higher in h-PTC than h-BTN, both in MNG (82.5% vs 45.0%, p<0.001) and S/I (85.6% vs 71.0%, p<0.001), but a higher number of patients with h-PTC had negative circulating TAb, despite the presence of moderate/severe LI. CONCLUSIONS: TAb are weakly associated to PTC in males and young females, while they are more frequent in older females with BTN. The frequency and severity of LI is significantly higher in PTC than in BTN, but in cancer patients TAb are frequently negative, despite the evidence of histological thyroiditis. These data suggest that different kinds of immune response may be involved in PTC and BTN.

Lower levels of TSH are associated with a lower risk of papillary thyroid cancer in patients with thyroid nodular disease: thyroid autonomy may play a protective role.

Higher TSH values, even within normal ranges, have been associated with a greater risk of thyroid malignancy. The relationship between TSH and papillary thyroid cancer (PTC) has been analyzed in 10 178 patients submitted to fine needle aspiration of thyroid nodules with a cytology of PTC (n=497) or benign thyroid nodular disease (BTND, n=9681). In 942 patients, submitted to surgery (521 from BTND and 421 from PTC), the histological diagnosis confirmed an elevated specificity (99.6%) and sensitivity (98.1%) of cytology. TSH levels were significantly higher in PTC than in BTND both in the cytological and histological series and also in patients with a clinical diagnosis of multinodular goiter (MNG) and single/isolate nodule (S/I). A significant age-dependent development of thyroid autonomy (TSH <0.4 microU/ml) was observed in patients with benign thyroid disease, but not in those with PTC, diagnosed both on cytology and histology. In patients with MNG, the frequency of thyroid autonomy was higher and the risk of PTC was lower compared to those with S/I. In all patients, the presence of thyroid auto-antibodies (TAb) was associated with a significant increase of TSH. However, both in TAb positive and TAb negative patients TSH levels were significantly higher in PTC than in BTND. Our data confirm a direct relationship between TSH levels and risk of PTC in patients with nodular thyroid diseases. Thyroid autonomy conceivably protects against the risk of PTC, while thyroid autoimmunity does not play a significant role.

Thyroid fine needle aspiration: how to improve clinicians' confidence and performance with the technique.

Studies from single institutions report an acceptable accuracy rate for thyroid fine needle aspiration (FNA). However, FNA accuracy is much lower in many other centers in Europe and the USA and large multicenter studies indicate that the clinicians' confidence in the FNA technique remains low. One explanation for this is that there is an excess of inadequate and indeterminate findings for a follicular nodule at FNA cytology. In a University Hospital with large and qualified experience on thyroid nodule diagnosis, a review of 320 slides with an FNA diagnosis of indeterminate follicular nodule from different minor Italian Hospitals led to a different diagnosis in 61%. Since ancillary thyroid imaging may be overutilized and only a few authors report a proportion of excised nodules lower than 10%, we suspect that use of the FNA procedure is suboptimal. Several techniques are reported to improve the performance of thyroid FNA. Among these are tumor markers and large needle aspiration biopsy (LNAB). Immunodetection of the tumor marker galectin-3 has been evaluated by large multinational studies. Analysis of LNAB specimens reduces the number of inadequate FNA findings, improves the diagnostic determination of indeterminate follicular FNA findings and represents a better substrate for the determination of galectin-3. Therefore, we propose that clinical practice guidelines reflect these adjuvant techniques to thyroid FNA in order to improve selection criteria for thyroid nodule surgery.

Correlation of recurrence rates and times with posttreatment human papillomavirus status in patients treated with loop electrosurgical excision procedure conization for cervical squamous intraepithelial lesions.

The aim of the present study was to assess recurrence rates and times in patients with squamous intraepithelial lesion (SIL) of the uterine cervix treated with loop electrosurgical excision procedure (LEEP) conization, in order to define categories of patients who have a different risk of recurrence and who need a different surveillance protocol. This study was carried out on 119 consecutive patients who underwent LEEP. All patients were followed up with cervical smear and colposcopy after 3, 6, and 12 months in the first-year posttreatment, and every 6-12 months afterwards. Human papillomavirus (HPV) testing was performed at the time of LEEP and repeated 3-6 months later. The histologic examination of LEEP specimens revealed stage IA1 squamous cell cervical cancer in 4 (3.4%) cases, high-grade SIL in 75 (63%) cases, and low-grade SIL in 40 (33.6%) cases. The four patients with stage IA1 cervical cancer were not included in the further analyses. Disease recurred in none of the 50 patients with negative posttreatment HPV testing, in 4 (9.3%) of the 43 patients with positive posttreatment HPV testing and negative surgical margins, and in 8 (36.4%) of 22 patients with positive posttreatment HPV testing and positive margins. The combined evaluation of surgical margin status and posttreatment HPV testing could allow to subdivide patients treated with LEEP into categories at different risk of recurrence, requiring new tailored surveillance procedures.

Clinical features of thyroid autoimmunity are associated with thyroiditis on histology and are not predictive of malignancy in 570 patients with indeterminate nodules on cytology who had a thyroidectomy.

BACKGROUND: The relationship between thyroid autoimmunity and cancer is still uncertain. PATIENTS: We approached this issue in 570 consecutive patients submitted to thyroidectomy for an indeterminate nodule on cytology. Thyroid autoimmunity was defined as positivity of circulating thyroid autoantibodies (TAb), autoimmune hypo- or hyperthyroidism, thyroid hypoechogenicity on ultrasound, and lymphocytic infiltration on histology. RESULTS: TAb were found in 122/570 (21.4%), hypoechogenicity in 115/570 (20.1%), and lymphocytic infiltration in 117/570 (20.5%) of patients. The three features of thyroid autoimmunity were highly concordant: hypoechogenicity was observed in 71/448 (15.8%) patients with negative TAb and in 44/122 (36%) with positive TAb (P < 0.0001); lymphocytic infiltration was found in 53/448 (11.8%) patients with negative TAb and in 64/122 (52.4%) with positive TAb (P < 0.0001); hypoechogenicity on ultrasound was observed in 73/453 (16.1%) patients without, and in 42/117 (35.9%) with lymphocytic infiltration (P < 0.0001). None of these parameters was associated with malignancy. TAb were found in 32/135 (23.7%) patients with carcinoma and in 90/435 (20.6%) with a benign lesion (P = NS); hypoechogenicity was observed in 26/135 (19.2%) patients with carcinoma and in 89/435 (20.4%) patients with benign lesions (P = NS); lymphocytic infiltration was present in 28/135 (20.7%) patients with carcinoma and in 89/435 (20.4%) with benign lesions (P = NS). The frequency of cancer in 11 patients with clinically overt thyroid autoimmune disease did not differ from that observed in the whole study group. CONCLUSION: In this group of patients with indeterminate thyroid nodules at cytology, clinical and pathological criteria of thyroid autoimmunity were strongly concordant and not associated with malignancy.

Combined clinical, thyroid ultrasound and cytological features help to predict thyroid malignancy in follicular and Hupsilonrthle cell thyroid lesions: results from a series of 505 consecutive patients.

OBJECTIVE: The cytological patterns of follicular and Hupsilonrthle cell nodules are included among the indeterminate results of fine-needle aspiration cytology, because distinction between benign and malignant lesion can only be made on histological criteria. The diagnostic value of atypia at cytology, clinical parameters and echographic patterns were examined to establish the risk of malignancy in 505 patients with follicular and Hupsilonrthle cell thyroid nodules at cytology. DESIGN AND PATIENTS: The study included 505 consecutive patients who had undergone thyroidectomy from the period 2002-2005. RESULTS: Histological diagnosis of malignancy was carried out in 125 of 505 (25%) patients, the follicular variant of papillary carcinoma being the most frequent histotype. Only atypia at cytology (P < 0.0001) and spot microcalcifications at ultrasound (P = 0.009) were predictive of malignancy. Male gender, normal thyroid volume, single nodularity, nodule hypoechogenicity, size and blurred margins were associated with malignancy, although not significantly. An arbitrary clinical score allowed the identification of patients with high (41%, 110 patients) and low (16%, 242 patients) risk of malignancy. Combining the clinical score with the presence of atypia at cytology we could identify 30 patients (6%) in whom the risk of malignancy was as high as 63%. CONCLUSIONS: Twenty-five per cent of patients with a cytological result of follicular and Hupsilonrthle cell thyroid lesion had a final diagnosis of malignancy. Only atypia at cytology and spot microcalcifications at thyroid ultrasound were significantly associated with malignancy. Other clinical parameters and thyroid ultrasound patterns can be used to set up a clinical score useful for predicting the individual risk of malignancy before surgery.

HPV testing and Pap test: role for a combined approach in a non-screened population.

The aim of the present study was to test the polymerase chain reaction (PCR) as a tool to identify human papillomavirus (HPV) in routine cytological samples scraped from the uterine cervix. Moreover, attention has been focused on the correlation between HPV types and early intraepithelial lesions. The study involved 586 women who had undergone conventional Pap test. Analysis of HPV infection was performed by PCR and HPV typing by dot blot. In a group of 78 cases histologically diagnosed as high-grade squamous intraepithelial lesions (HSILs), the cytological diagnosis was correct in 92.3% and the HPV test was positive in 89.8% of cases; combined positivity at Pap and/or HPV tests raised this figure to 99.0%. In a group of 67 cases histologically diagnosed as low-grade squamous intraepithelial lesions (LSILs), the cytological diagnosis was correct in 73.1% and the PCR-based HPV test was positive in 64.2%; combined positivity at Pap and/or HPV tests raised this figure to 91.0%. This study confirms the limitations of screening programs based on Pap test only. Our results suggest, in fact, that adding the HPV test to primary screening could increase the yield of preinvasive cervical lesions.

Large-needle aspiration biopsy for the preoperative selection of palpable thyroid nodules diagnosed by fine-needle aspiration as a microfollicular nodule or suspected cancer.

The palpable thyroid nodules with a fine-needle aspiration (FNA) diagnosis of microfollicular nodule or suspected cancer usually are excised; however, most of them are proved benign by postoperative histologic examination. We reviewed the clinical and pathologic data for patients with thyroid nodules with an FNA diagnosis of microfollicular nodule or suspected cancer; nodules also were examined by large-needle aspiration biopsy (LNAB) to assess whether the distinction achieved by LNAB into pure microfollicular or mixed microfollicular-macrofollicular nodules could be used preoperatively to better predict malignancy. One hundred fourteen nodules of this type were excised. The prevalence of cancer was 22% (14/63) among the microfollicular and 4% (2/51) among the microfollicular-macrofollicular nodules at LNAB. These data indicate that histologic examination of the LNAB specimen can be used for preoperative selection of thyroid nodules diagnosed by FNA as a microfollicular nodule or suspected cancer.

Aspiration needle biopsy in preoperative selection of thyroid nodules defined at fine-needle aspiration as microfollicular lesions.

The palpable thyroid nodules that are diagnosed as microfollicular by fine-needle aspiration cytologic analysis are usually excised for the low probability that the nodule is a well-differentiated follicular cancer. The authors retrospectively assess the use of aspiration needle biopsy (either 16- or 18-gauge needles) in the preoperative selection of the nodules diagnosed as microfollicular at fine-needle aspiration (either 20- or 22-gauge needles). Aspiration needle biopsy is a type of large needle biopsy that is a relatively easy and innocuous method of obtaining tissue fragments for preoperative histologic examination of palpable thyroid nodules. From 1980 through 1996, 6,314 patients with palpable thyroid nodules were examined by fine-needle aspiration; 29.5% of these nodules were also examined preoperatively by aspiration needle biopsy. Of all the patients with nodules, 6% received a fine-needle aspiration diagnosis of microfollicular nodule. Two hundred sixty of the 380 nodules (68%) that were diagnosed as microfollicular at fine-needle aspiration were also examined by aspiration needle biopsy; inadequate specimens were obtained in 17% of cases; pure microfollicular structure was confirmed by aspiration needle biopsy in 35% of the nodules; and aspiration needle biopsy showed the remaining 48% to contain a macrofollicular component suggesting a benign hyperplastic lesion. Seventeen nodules that were found to be microfollicular at fine-needle aspiration cytologic analysis and micromacrofollicular at aspiration needle biopsy were excised and the postoperative result was benign in all cases. Twenty-five nodules diagnosed as microfollicular either on both fine-needle aspiration and aspiration needle biopsy were excised and the postoperative diagnoses were benign (20 nodules) or malignant (5 nodules). These data indicate that aspiration needle biopsy can be used for preoperative selection of the nodules that are microfollicular at fine-needle aspiration by identifying the nodules with high probability of being malignant and thus contributing to the reduction in the number of surgical operations for benign nodules.

Large needle aspiration biopsy for reducing the rate of inadequate cytology on fine needle aspiration specimens from palpable thyroid nodules.

From 1980 to 1996, 1,907 consecutive euthyroid subjects with palpable thyroid nodules were examined by fine needle aspiration (FNA) cytology plus large needle aspiration biopsy (LNAB) histology. There were 1,630 (85%) women and 277 (14.5%) men aged from 17 to 80 years. A single nodule was palpated in 1,419 subjects (74.4%) while 488 (25.6%) showed multiple nodules. The nodule size ranged between 1 and 7.5 cm. The number of inadequate specimens at the first examination, FNA cytology of LNAB histology, were 261 (13%) or 398 (20.8%), respectively. LNAB performed on the 261 nodules with nondiagnostic cytology showed findings which were adequate for diagnosis in 130 (49.8%) and inadequate in 131 (50.2%). Among the 261 patients with inadequate initial cytological findings 61 were subjected to repeated FNA and 36 repeated LNAB. More than 60% of the nodules on which FNA was repeated achieved a cytological diagnosis; more than 80% of the nodules reinvestigated by LNAB were finally diagnosed by histology. The mean nodule size was larger in the group with inadequate result than in that with adequate FNA or LNAB result. Among the 261 patients with inadequate cytological finding at the first FNA 28 were operated on; 20 were in the group with adequate LNAB histological findings and eight in the group with an inadequate LNAB. Two papillary cancers, one per group, were found at postoperative histology. However, one was diagnosed by LNAB and one at the second FNA. The remaining 26 nodules were all found to be benign postoperatively. This study shows that the addition of LNAB to FNA leads to a histological diagnosis in 50% of the palpable thyroid nodules with inadequate cytology at the first FNA and that LNAB can be used even for those nodules which remain uncharacterized after repeat FNA.

Needle aspiration techniques in preoperative selection of patients with thyroid nodules: a long-term study.

PURPOSE: Long-term evaluation of the combination of two needle aspiration techniques (NAT) (fine-needle aspiration [FNA] and aspiration needle biopsy [ANB]) in performing an efficient preoperative selection of palpable thyroid nodules. PATIENTS AND METHODS: Eight years of extensive use of surgery for the detection of thyroid cancer was compared with 12 years of preoperative selection of by NAT. RESULTS: A total of 1,140 operations were performed from 1972 to 1979, and 35 malignant nodules were discovered (3.1%). Five thousand four hundred three patients were examined by NAT from 1980 to 1992; 483 (9%) underwent surgery and 158 malignant nodules were excised. The number of malignant nodules identified by NAT was 166 (eight were not excised) (3.1% of the total population examined). The principal clinical and pathologic features were similar in both groups. ANB yielded a definite benign diagnosis in 88 patients with inadequate FNA findings, it correctly identified four malignant nodules diagnosed as benign by FNA, it showed a macrofollicular component in 115 nodules diagnosed by FNA as microfollicular nodules, and it significantly changed the predictive value of 79 suspicions FNA diagnoses. CONCLUSION: Introduction of NAT reduced the number of operations for palpable thyroid nodules from 143 to 40 per year and increased from four to 13 the number of malignant nodules excised without any change in the overall incidence of malignant nodules. The combination of ANB to FNA significantly contributed to the high and efficient preoperative patient selection, principally by reducing the number of indeterminate or suspicious, as well as false-negative, preoperative FNA diagnoses.

Aspiration needle biopsy refines preoperative diagnosis of thyroid nodules defined at fine needle aspiration as microfollicular nodule.

The aim of this paper was to verify the hypothesis that large needle biopsy performed preoperatively can refine preoperative fine needle aspiration (FNA) cytological diagnoses of microfollicular nodules. Since 1980 we have been using FNA and aspiration needle biopsy (ANB) (18 or 16 gauge needles) to select for surgery all euthyroid patients with palpable thyroid nodules referred to our department. From 1980 to 1994, 6,124 patients (12% male, 88% female) with thyroid nodules (71% single, 29% multiple) were examined by FNA; 29% of these patients were also examined preoperatively by ANB histology. Of all the nodule patients examined, 371 received a preoperative FNA diagnosis of microfollicular nodule. Two hundred and fifty-four of these nodules (68%) were also examined preoperatively by ANB. Unsatisfactory ANB specimens constituted 17% of cases; pure microfollicular structure was confirmed by ANB in 36% of the nodules; ANB showed the remaining 47% to contain a macrofollicular component, thus suggesting a benign hyperplastic lesion. Twelve nodules which were found to be microfollicular at FNA cytology and micro-macrofollicular at ANB were excised and were subsequently determined as benign at definitive postoperative histology. These data indicate the utility of ANB in refining the preoperative FNA diagnosis of microfollicular nodule and in preoperatively identifying benign hyperplastic mixed micro-macrofollicular lesions which can be followed by observation.

Presence of endothelin-1 in the normal and pathological human thyroid.

An immunohistochemical study with two rabbit polyclonal antibodies I-AR76 and CA-08-351 against Endothelin-1 (ET-1) was performed in 133 human thyroid specimens: 5 normal thyroids, 30 multinodular goiters (15 toxic and 15 nontoxic), 20 Graves' diseases, 5 Hashimoto's thyroiditis, 26 adenomas (6 Hürthle cell, 16 toxic and 4 nontoxic), 30 classic papillary carcinomas, 3 minimally invasive follicular carcinomas, 1 widely invasive follicular carcinoma, 3 undifferentiated carcinomas and 10 medullary carcinoma. All normal thyroids, non toxic multinodular goiters and non toxic adenomas, 4 (66%) Hürthle cell adenomas, 3 (15%) Graves' diseases, 1 (33%) case of minimally invasive follicular carcinoma showed rare follicular cells with weak cytoplasmic immunoreactivity. Many immunoreactive follicular cells, with or without oxyphilic changes, were observed in all specimens of Hashimoto's disease, while the lymphocytic infiltrate was always negative. Twenty-seven (90%) classic papillary carcinomas were positive. Immunoreactivity was intracytoplasmic, weak in 14 cases and intense in 13. The cells of toxic adenoma and toxic multinodular goiter were negative, whereas the acellular stroma was intensely positive in both cases. Medullary and undifferentiated carcinomas were negative. These results show ET-1 immunoreactivity in normal and pathological human thyroids. In particular, the high content of this peptide in the thyroid papillary carcinoma suggests that ET-1, whose mitogenic role has recently been emphasized, could be involved in the growth of this tumor.

Role of neck ultrasonography in the follow-up of patients operated on for thyroid cancer.

The aim of the study was to evaluate the role of neck ultrasonography in follow-up of patients with differentiated thyroid cancer. Sixty-three patients had total thyroidectomy and 131I ablation for differentiated thyroid cancer and had a negative whole body scan during follow-up. They were admitted for a high resolution neck ultrasound examination. Sixteen of 63 patients presented images suspicious for lymph node metastasis and/or for local recurrences (4 cases). Fine needle aspiration confirmed the suspicion of malignancy in 12 patients: only lymph node metastasis in 8 cases, local recurrence and lymph node metastasis in 3 cases, and in one case only local recurrence. Fine needle aspiration was suspicious for lymphadenitis in 4 cases. Thyroglobulin levels were very high in all patients with local recurrence and/or lymph node metastasis but undetectable in 2 cases presenting node metastasis and in 4 cases with lymphadenitis. All but one patient were admitted for surgery and the cytological diagnosis was confirmed. Early identification of a pathologic mass in the neck is a desirable goal; high resolution echography can play an important role in the follow-up of these patients and can detect local recurrences even when there is a negative whole body scan or undetectable thyroglobulin level.